Oxygenated n,2,3,3-tetramethyl-exo-2-norbornanamines

ABSTRACT

This invention relates to a novel microbiological process for the oxygenation of N-benzoyl-N,2,3,3-tetramethyl-exo-2norbornanamine to obtain N-benzoyl-exo-6-hydroxy-N,2,3,3tetramethyl-exo-2-norbornanamine and N-benzoyl-trans-7-hydroxy-N, 2,3,3-tetramethyl-exo-2-norbornanamine, each of which are chemically converted to novel derivatives. These novel bioconversion products and their derivatives are active hypotensive agents and central nervous system stimulants.

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err et al.

[ 1 OXYGENATED N,2,3,3-

TETRAMETHYL-EXO-Z- NORBOANAMIINES [75] Inventors: Milton E. Herr,Kalamazoo; Herbert C. Murray, Hickory Comers; Gunther S. Fonken,Charleston Township, all of Mich.

[73] Assignee: The Upjohn Co., Kalamazoo, Mich.

[22] Filed: July 15, 1370 [21] Appl. No.: 55,272

[52] U.S. Cl. ..260/2955 S, 195/29, 260/404, 260/456, 260/468 R, 260/468P, 260/469,

260/475 R, 260/476 C, 260/478, 260/486 R,

260/488 B, 260/50l.1, 260/50l.2l, 260/558 424/314, 424/324, 424/325 [51]Int. Cl ..C07e 87/40 [58] Field of Search ..260/563 P, 295.5 S

[56] References Cited UNITED STATES PATENTS 2,831,027 4/1958 Pfister etal. ..260/563 P Feb.,20,1973

FOREIGN PATENTS OR APPLICATIONS 827,832 1960 Great Britain ..260/563 POTHER PUBLICATIONS Tanida et al.; J.A.C.S. Vol. 89 (1967), pp. 1953-1954Primary ExaminerLewis Gotts Assistant ExaminerD. R. PhillipsAttorney-John Kekich and Ward F. Nixon [57] ABSTRACT This inventionrelates to a novel microbiological process for the oxygenation ofN-benzoyl-N,2,3,3-

active 'hypotensive agents and central nervous system stimulants.

27 Claims, No Drawings OXYGEN ATED N ,2,3 ,3-TETRAMETIIYL-EXO-2-NORBORNANAMINES SUMMARY OF THE INVENTION The novel compounds of thisinvention are illustratively represented by the following structuralformulas:

NR R1- H;

on, OH:

i i NR N-R 0: 40m (0H;

and TCH: on: on,

tion, the 7-trans configuration and mixtures thereof.

The 7-cis and 7-trans configurations are relative to the 2-methylaminogroup.

The novel compounds of this invention represented by formulae A, B, Cand D, above, and the pharmacologically acceptable acid addition saltsof the basic compounds of formulas A, B, C and D, wherein R is hydrogenor benzyl, have ganglionic blocking activity and are useful hypotensiveagents; they are also central nervous system stimulants. As hypotensiveagents they are useful for lowering blood pressure, and as centralnervous system stimulants they are mood elevators and psychic energizerswhich are useful in the treatment of mental health conditions.

The novel compounds of this invention and the phar-- macologicallyacceptable acid addition salts thereof are useful in the treatment ofanimals and birds, and are particularly useful in the treatment ofhumans and valuable domestic animals. They can be administered as activeingredients in conventional pharmaceutical forms such as tablets,capsules, elixirs, injectable solutions and suspensions.

Additionally, the free bases of formulae A, B, C and D wherein R ishydrogen or benzyl form salts with nanamine to the oxygenating activityof the microorganism Sporotrichum sulfurescens to obtainN-benzoylexo-6-hydroxy-N ,2,3 ,3-tetramethyl-exo-Z-norbornanaminetetramethyl-exo-2-norbomanamine, each of which are converted to theother novel compounds of this invention in accordance with methods knownin the art.

DETAILED DESCRIPTION OF THE INVENTION The microbiological process ofthis invention is represented by the following reaction scheme:

0 01130 Q NC N- The microbiological process of this invention comprisessubjecting N-benzoyl-N,2,3,3-tetramethyl-exo-2- norbornanamine (I) tothe oxygenating activity of the microorganism Sporotrichum sulfurescens,to obtain N-benzoyl-exo-6-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine (II) anN-benzoyl-trans-7-hydroxy- N,2,3,3-tetramethyl-exo-Z-norbornanamine(III).

The genus Sporotrichum belongs to the family Moniliaceae of the orderMoniliales of the class Deuteromycetes. The typical strain preferred forthe practice of this invention is Sporotrichum sulfurescens, CollectionNo. ATCC 7159; available from the American Type Culture Collection(ATCC), Washington, D. C. It is to be understood that other strains ofthese microorganisms are suitable for the practice of this invention.

The starting material (I) for the microbiological process of thisinvention is prepared by treatingN,2,3,3-tetramethyl-exo-2-norbornanamine, hydrochloride (mecamylamine,hydrochloride) with dilute sodium hydroxide followed by treatment withbenzoyl chloride in accordance with Preparation 1, herein, to obtainN-benzoyl-N,2,3,3-tetramethyl-exo-2- norbornanamine (I).

g The operational conditions and reaction procedures for bioconversionprocess of this invention are advantageously those known in the art ofbioconversion as illustrated in Murray et al., U. S. Pat. Nos. 2,602,769and 2,735,800, utilizing the oxygenating activity of the microorganismSporotrichum sulfurescens.

In the practice of this invention, the bioconversion can be effected bya growing or resting culture of the andN-benzoyl-trans-7-hydroxy-N,2,3,3--

microorganism or by spores, washed cells or enzymes of themicroorganism.

Culture of the microorganism for the purpose and practice of thisinvention is in or on a medium favorable to its development. Sources ofnitrogen and carbon should be present in the culture medium and anadequate sterile air supply should be maintained during the conversion,for example, by the conventional techniques of exposing a large surfaceof the medium or by passing air through a submerged culture.

Nitrogen in assimilable form can be provided by sources normallyemployed in such processes, such as corn steep liquor, soybean meal,yeast extracts, peptone, soluble or insoluble vegetable or animalprotein, lactalbumin, casein, whey, distillers solubles, amino acids,nitrates and ammonium compounds, such as ammonium tartrate, nitrate,sulfate and the like.

Available carbon can also be provided by sources normally used inbioconversions such as carbohydrates, e.g., glucose, fructose, sucrose,lactose, maltose, dextriries, starches: meat extracts, peptones, aminoacids, proteins, fatty acids, glycerol, whey and the like. Thesematerials may be used either in a purified state or as concentrates suchas whey concentrate, corn steep liquor, grain mashes, and the like, oras mixtures of the above. Many of the above sources of carbon can alsoserve asa source of nitrogen.

The medium can desirably have a pH before inoculation of between about 4to about 7 though a higher or lower pH can be used. A temperaturebetween about 25 to 32 C. is preferred for growth of the microorganismbut higher or lower temperatures within a relatively wide range aresuitable.

The substrate (1) can be added to the culture during the growth periodof the microorganism as a single feed or by gradual addition during theconversion period, or

it can be added to the medium before or after sterilization orinoculation making appropriate adjustments for effects of pH and/ortemperature uponthe stability of the substrate. The preferred, but notlimiting, range of concentration of the substrate in the culture mediumis about 0.1 to grams per liter. The substrate is added to the medium inany suitable manner, especially one which promotes a large surfacecontact of the substrate to the oxidizing activity of the microorganism,for example by dissolving the substrate in an organic solvent and mixingthe solution thoroughly with the medium or by adding to the mediumfinely comminuted particles of the substrate, e.g., micronizedparticles, preferably 90 percent by weight smaller than 20 microns,either as a dry powder or, preferably for mechanical reasons, as anaqueous suspension. In preparing the aqueous suspension, the-use ofdispersing or suspending agents is advantageous. Dispersing agents canalso be added to the medium.

The temperature duringthe fermentation can be the same as that foundsuitable for growth of the microorganism. It need be maintained onlywithin such range as supports life, active growth or the enzyme activityof the microorganism, the range of 20 to 30 C. is preferred. A pH ofabout 4 to 8 is generally preferred for growth of the microorganismduring the bioconversion. Aeration can be effected by surface culture orpreferably under submerged fermentation conditions, in accordance withmethods well known in the art. The time required for oxygenation by theenzymatic system of the microorganism employed can vary considerably.The range of about 2 to 120 hours is practical but not limiting; 72hours is generally satisfactory. The progress of the bioconversion andits completion are conveniently determined by paper-stripchromatography, vapor-phase chromatography, or thin-film chromatography[l-laftman, Chromatography (1961) Reinhold Publishing Co., New York, NewYork].

Alternatively, the oxygenation of the selected substrate can be effectedunder aerobic conditions by subjecting it to the oxygenating action ofoxygenating enzymes isolated from the microorganism, to the action ofspores of the microorganism, and to the action of isolated cells of themicroorganism. Isolated enzyme preparations can be prepared inaccordance with the general procedure disclosed by Zuidweg et a1.,Biochim. Biophy. Acts, 58, 131-133 (1962). Oxygenation can be effectedwith spores in accordance with the general process disclosed in U. S.Pat. Nos. 3,031,379 and 3,031,382. The separation of washed cells fromthe fermentation medium is well known in the art, see for example, U. S.Pat. No. 2,831,789.

The term oxygenating activity as used throughout this specificationmeans the enzymatic action of a growing or resting culture of themicroorganism or of spores, washed cells or isolated enzymes of themicroorganism, which effects introduction of oxygen in the molecule ofthe substrate under aerobic fermentation conditions.

After completion of the fermentation, the resulting oxygenated products(11) and (Ill) are recovered from the fermentation beer by conventionalmethods. For example, the whole beer can be extracted with awaterimmiscible organic solvent such as methylene chloride, chloroform,carbon tetrachloride, ethylene chloride, trichloroethylene, ether, amylacetate, benzene, and the like or the beer and mycelia can be separatedby conventional methods such as centrifugation or filtration, and thenseparately extracted with suitable solvents. The mycelia can beextracted with either watermiscible or water-immiscible solvents or incases where little or no product is contained in the mycelium, item bemerely washed with water and the wash water added to the beer filtrate.The beer, free of mycelia, can then be extracted with water-immisciblesolvents such as those listed above. The extracts are combined,'driedover a drying agent such as anhydrous sodium sulfate, and the solventremoved by conventional methods such as evaporation or distillation atatmospheric or reduced pressure.

Alternatively, the products can be adsorbed from the beer on granularcharcoal and the products eluted with a polar organic solvent such asmethanol, ethanol, acetone, ethyl acetate, and the like.

The compounds of formulae (II) and (III) are converted to the othercompounds of this invention in accordance with the following reactionschemes:

SCHEMES I AND 2 The compounds (II) and (III), obtained from thebioconversion process of this invention are oxidized to obtain thecorresponding keto compounds of formulae (IV) and (IX) respectively, inaccordance with methods known in the art for oxidizing secondary hydroxygroups to ketones, for example, Fieser and Fieser, Natural ProductsRelated to Phenanthrene, 3rd. Ed., pages 127429, Reinhold PublishingCorporation, New York, New York. Thus, the selected compound (II) or(III) is dissolved in an inert organic solvent such as acetone, benzene,methylene chloride, t-butanol, and the like, and then oxidized withaqueous chromic acid, e.g., Jones reagent, to convert the hydroxy groupto keto. The corresponding keto compounds (IV) and (IX) thus obtained,are recovered from the reaction mixture and purified by conventionalmethods. For example, extraction with an organic solvent, e.g.,methylene chloride followed by recrystallization from a suitable organicsolvent, e.g., acetone, benzene, methylene chloride, hexanes, mixturesthereof, and the like.

The keto compounds (IV) and (IX) thus obtained are selectively reducedat the ring attached keto group in accordance with methods well known inthe art, for example, using sodium or potassium borohydride to obtainthe corresponding endo-o-hydroxy and cis-7- hydroxy compounds offormulae (V) and (X), respectively, which are separated from thereaction mixture and purified by conventional methods such ascrystallization, chromatography and the like. Alternatively, thecompounds of formulae (IV) and (IX) can also be reduced at both the ringketo group and the amido group by known methods, for example, usinglithium aluminum hydride to obtain the corresponding benzylamines offormulae (VI) and (XI), respectively.

The hydroxy benzamides of formulae (II), (V), (III) and (X) are reducedin accordance with methods known in the art for reducing amides toamines to obtain the corresponding hydroxy benzylamines of formulae(VII), (VI), (XII) and (XI) respectively. The reduction is preferablycarried out using lithium aluminum hydride as the reducing agent. Thereduction reaction is carried out in the presence of an inert organicsolvent such as ether, tetrahydrofuran, benzene, diglyme, combinationsthereof and the like. The reduction reaction is preferably conducted atreflux temperature and a period of about 1 to about 4 hours depending onthe solvent employed is generally sufficient for completion of thereaction. The hydroxybenzylamines thus obtained are recovered as thefree bases by conventional methods and are purified if desired bydistillation. Alternatively, the hydroxybenzylamines can be recoveredand purified by preparation of the acid addition salts thereof inaccordance with methods hereinafter described.

The hydroxybenzylarnines of formulae (VII) and (VI) and formulae (XII)and (XI) thus obtained, are converted to the corresponding norbornaminesof formulae (VIII) and (XIII) respectively by catalytic hydrogenoiysisin accordance with methods known in the art [organic Reaction, Vol. VII,p. 277, John Wiley & Sons, Inc., New York (1953)], for example usinghydrogen and paladium on carbon catalyst. The compounds of formulae(VIII) and (XIII) are recovered from the reaction mixture byconventional methods, such as removal of catalyst by filtration,extraction with a suitable organic solvent followed by chromatographyand/or crystallization. Alternatively the compounds of formulae (VIII)and (XIII) are recovered as the acid addition salts as hereinafterdescribed.

SCHEME 3 The G-hydroxy compounds of formulae (VI), (VII) and (VIII)represented collectively by formula (XIV) and the 7-hydroxy compounds offormulae (XI), (XII) and (XIII) represented collectively by formula (XV)are oxidized using an Oppenauer oxidation,- for example, using a ketone,such as acetone or cyclohexanone and an aluminum alkoxide, such asaluminum isopropoxide in an organic solvent, e.g., benzene or toluene toobtain the corresponding keto-amines of formulae (XVI) and (XVII),respectively. The ketoamines are recovered from the reaction mixture byconventional methods, for example, first neutralizing or acidifying thereaction mixture with a mineral acid, e.g., hydrochloric acid,extracting the mixture thus obtained with a suitable organic solvent,e.g., benzene, toluene, ether, methylene chloride and the like, toremove organic impurities. The aqueous layer is then made basic, forexample, with sodium or potassium hydroxide and the product is extractedwith ether or other suitable organic solvent and the solvent is removedby evaporation or distillation. Alternatively, the keto-amines offormulae (XVI) and (XVII) can be recovered as their acid addition saltsas hereinafter described.

Alternatively the compounds of formulae (XVI) and (XVII) wherein R ishydrogen are prepared from the corresponding compounds of formulae (XVI)and (X- VII), respectively, wherein R is benzyl, by catalytichydrogenolysis as hereintofore described.

SCHEME 4 The compounds of formulae (II) and (V), representedcollectively by formula XVIII and the compounds of formulae (III) and(X), represented collectively by formula (XIX) are converted to theircorresponding methoxy derivatives of formulae (XX) and (XXI),respectively, in accordance with methods known in the art. The selectedcompound of formulae (XVIII) or (XIX) is treated with aluminumisopropoxide and diazomethane using the method of A. Popelak and G.Lettenbauer, Arch. Pharmay. 295, 427 (1962) to obtain the correspondingmethoxy compounds of Formulas (XX) and (XXI), respectively, which areisolated and recovered from the reaction mixture by conventional methodssuch as chromatography and/or crystallization from a suitable solvent.

The compounds of formulas (XX) and (XXI) thus obtained are reduced tothe corresponding benzyl compounds of formulae (XXII) and (XXIII),respectively, with lithium aluminum hydride as hereintofore disclosedunder Schemes l and 2, above, for example, the reduction of compound(II) to compound (VII).

The compounds of formulae (XXII) and (XXIII) thus obtained are thensubjected to catalytic hydrogenolysis in accordance with the methodhereintofore disclosed to obtain the corresponding secondary amines offormulae (XXIV) and (XXV), respectively.

Acyl derivatives of the compounds of formulae (II), and

IH) of this invention are prepared in accordance with methods commonlyused for preparing steroid acylates, for example by treating theselected hydroxy compound in pyridine with excess acid anhydride or acidchloride at about room temperature for 1-24 hours, or by heating theselected compound with an acid anhydride in the presence of an alkaliearth carbonate such as calcium carbonate. Acylating agents which can beemployed are for example the anhydrides and chlorides or organiccarboxylic acids, preferably hydrocarbon carboxylic acids of one to 12carbon atoms, inclusive, such as acetic, propionic, butyric, isobutyric,pivalic, valeric, isovaleric, caproic, caprylic, decanoic, dodecanoic,acrylic, crotonic, hexynoic, heptynoic, octynoic, cyclobutanecarboxylic,cyclopentenecarboxylic, cyclohexanecarboxylic,dimethylcyclohexanecarboxylic, benzoic, toluic, naphthoic, ethylbenzoic,phenylacetic, naphthaleneacetic, phenylvaleric, cinnamic,phenylpropiolic, phenylpropionic, pbutoxyphenylpropionic, succinic,glutaric, dimethylglutaric, maleic, cyclopentylpropionic,p-toluenesulfonic acids, and the like.

The compounds of formulae (VIII) and (XIII) can in most instances beselectively acylated at either the 6 or 7-hydroxy group withoutconcommitantly forming the corresponding amides. If formation of theamide is a problem the 6- and 7-acylates of the compounds of formulae(VIII) and (XIII) can be prepared by catalytic hydrogenolysis of thecorresponding acylated benzylamines of formulae (VI), (VII), (XI) and(XII).

The free amines of formulae (VI), (VII), (VIII), (X), (XI), (XII),(XIII), (XVI), (XVII), (XXII), (XXIII), (XXIV) and (XXV) of thisinvention can be converted by known methods to their pharmacologicallyacceptable acid addition salts by treating the selected amine with theappropriate acid. Acids which can be used are, for example, sulfuric,hydrochloric, nitric, phosphoric, lactic, benzoic, methanesulfonic,p-toluenesulfonic, salicyclic, acetic, propionic, maleic, malic,tartaric, citric, cyclohexanesulfamic, succinic, nicotinic, ascorbic andlike acids, in the presence of an inert solvent such as methanol,ethanol, diethyl ether, ethyl acetate, and the like. 4

The following preparation and examples illustrate the best modecontemplated by the inventors for carrying out their invention, but arenot to be construed as limiting the scope thereof.

Preparation 1 N-benzoyl-N,2,3,3-tetramethyl-exo-2- norbornanamine (I) Amixture of 78.0 g. of N,2,3,3-tetramethyl-exo-2- norbornanaminehydrochloride, 600 ml. of 10 percent sodium hydroxide solution, and 48ml. of benzoyl chloride is stirred in an ice bath for about 1 hr. andthen at room temperature for about 1 hour. After adding 36 ml. more ofbenzoyl chloride, the mixture is stirred for 24 hours, extracted withether, the extract washed with water and dried over sodium sulfate. Thesolvent is removed and the residue crystallized by dissolving inmethanol and adding water. The solid is recovered, dried andrecrystallized from hexane; yield 98.0 g. ofN-benzoyl-N,2,3,3-tetramethyl-exo-2-norbornanamine (I), m.p. 64-65 C.

Example 1 N-benzoyl-exo-6-hydroxy-N-2,3,3-tetramethyl-exo-Z-norbornanamine (II) A medium is prepared of 40 g. ofcornsteep liquor (60percent solids), 20 g. of commercial dextrosediluted to 1 liter with tap water and adjusted to a pH of between 4.8and 5.0. One ml. of UCON LB 625 (Union Carbide) is added as an antifoamagent. One hundred liters of this medium is sterilized and inoculatedwith 72-hour vegetative growth of Sporotrichum sulfurescens, ATCC 7159,and incubated at about 28 C. with aeration at about 5 l. per minute andstirring at about 300 r.p.m. After about 43 hours, or when a moderate toheavy growth of mycelium is apparent, 250 ml. of ULRAWET DS 30 (ARCOChemical Co.) and a solution of 12 g. of N-benzoyl-N-2,3,3- tetramethylexo-2-norbornanamine (I) in about 200 ml. of N,N-dimethylformamide isadded to the fermentation. After an additional 72-hour period ofincubation, 1,500 g. of diatomaceous earth (Celite) is added and thebeer and mycelium are separated by filtration.

The beer thus obtained is extracted 4 times with 25 l. of methylenechloride. The extracts are filtered, dried over sodium sulfate andevaporated to remove the solvent. The residue thus obtained is taken upin 300 ml. of methylene chloride and chromatographed over a columncontaining 600 g. of Florasil (synthetic magnesium silicate). The columnis eluted by the linear gradient method with 18 l. of Skellysolve Bhydrocarbons containing increasing proportions of acetone from 0 to 18percent. Cuts of 325 ml. each are collected and the residues therefromexamined by thinlayer chromatography (TLC) which showed the presence ofN- benzoyl-exo-G-hydroxy-N,2,3,S-tetramethyl-exo-Z-norbornanamine (II)and N-benzoyl-trans-7-hydroxy- N,2,3,3-tetramethyl-exo-Z-norbornanamine(III). Those fractions containing N-benzoyl-exo-fi-hydroxy-N-2,3,3-tetrarnethyl-exo-2-norbornanamine are pooled and crystallizedfrom ether to give 3.05 g. (21 percent yield) ofN-benzoyl-exo-6-hydroxy-N-2 ,3 ,3 tetramethyl-exo-2-norbornanamine (II),m.p. 17818 0 C; an analytical sample recrystallized from methylenechloride ether, m.p. l-l 82 C;

Anal. Calcd. for C H NO C, 75.22; H, 8.77; N,

Found: C, 75.28; H, 8.86; N, 4.87.

Example 2 N-benzoyl-6-keto-N,2,3,3-tetramethylexo-2-norbornanarnine (IV)and N-benzoyl-7-keto- N,2,3,3-tetramethyl-exo-2-norbornanarnine (IX) Thebioconversion and extraction procedures of Example l, above, arerepeated using l. of sterilized medium of the same composition; themicroorganism Sporozrichum sulfurescens, ATCC 7159, and 30 g. of thesame substrate, N-benzoyl-N,2,3,3-tetramethylexo-Z-norbornanamine (1).Thin layer chromatographic analysis of the extract residues thusobtained shows the presence of N-benzoyl-exo-6-hydroxy-N2,3,3-tetramethyl-exo-2-norbornanamine (II) and N-benzoyl-trans-7-hydroxy-N,2,3,3-tetramethyl-exo-2- norbornanamine (111).

The residue extract obtained above, is dissolved in 500 m1. of acetoneand oxidized with 35.0 ml. of chromic acid solution (Jones reagent,prepared from 267 g. of chromic anhydride, 230 ml. of concentratedsulfuric acid and water sufficient to make 1 1.). The mixture is stirredfor five minutes; 10.0 ml. of isopropanol is added and the mixture isconcentrated under reduced pressure to about one-third volume, dilutedwith 500 ml. of water, and extracted several times with methylenechloride. The combined extracts are washed with water, dried over sodiumsulfate and concentrated to remove the solvent to obtain 30 g. of oil.The oil thus obtained is placed on a column containing 1,500 g. ofFlorisil. The column is eluted in cuts of 1 1. each with 4 1. each ofSkellysolve B hexanes containing 5%, 8%, 11%, 14% and 17% acetone. Thefractions are examined by TLC and those containing predominatelyN-benzoyl-6-keto--N,2,3,3-tetramethylexo-2-norbornanamine are combinedto give 7.62 g. (24 percent yield of N-benzoyl-6-keto-N,2,3,3-

tetramethyl-exo-2-norbornanamine (IV);'an analyticaltetramethyl-exo-2-norbomanamine (IV) in about 250 ml. of methanol isstirred with 10.0 g. of sodium borohydride in ml. of water for about 16hr. The mixture is chilled and carefully treated with 50 percent aqueousacetic acid until pH 6. Most of the methanol is then evaporated, themixture is diluted with 100 ml. of water, chilled, and the solidproductrecovered by filtration, washed with water, and dried, yield,14.84 g. of

' N-benzoyl-endo-6-hydroxy-N,2,3,3-tetramethyl-exo-2- norbornanamine(V), m.p. 223-227 C., recrystallized from methanol-water m.p. 23023 1 C.

Anal. Calcd. for C, H NO,: C, 75.22; H, 8.77; N,

Found: C, 75.32; H, 9.04; N, 5.11.

Example 4 N-b'enzoy1-cis-7-hydroxy-N-2,3,3-tetramethyl-exo-Z-norbornanamine (X) Following the procedure of Example3, above a solution of 6.0 g. ofN-benzoyl-7-keto-N,2,3,3-tetramethylexo-2-norbornanamine (V) in about100 m1. of methanol is treated with 5.0 g. of sodium borohydride in 25ml. of water to obtain 4.34 g. of N-benzoyl-cis-7-hydroxy-N-2,3,3-tetramethyl-exo-2-norbornanamine (X), m.p. l86188 C.; ananalytical sample recrystallized from acetone-water m.p. 186-187 C.

Anal. Calcd. for C H NO C, 75.22; H, 8.77; N,

Found: C, 75.46; H, 8.96; N, 4.84. Example 5N-benzyl-exo-6-hydroxy-N,2,3,3- tetramethyl-exo-2-norbornanamine (V11),and the hydrochloride salt thereof.

Five grams of N-benzoyl-exo-6-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine (11) in 100 ml. of anhydroustetrahydrofuran is added during 10 minutes with stirring to a mixture5.0 g. of lithium aluminum hydride and 100 m1. of ether. The mixture isrefluxed for minutes, chilled in a cold bath at -10 C. and cautiouslytreated with 25 ml. of water while stirring vigorously. When the mixtureis completely white, the inorganic solid is removed by filtration andwashed well with ether. The combined filtrate and wash are dried overmagnesium sulfate and the solvent is evaporated to yield 4.76 g. ofN-benzyl-exo-6-hydroxy-N,2,3,3- tetramethyl-exo-2-norbornanamine (V11),as a colorless oil. For testing purposes and for analysis this free baseis dissolved in ether and converted to its hydrochloride salt byaddition of a slight excess of ethereal l'lCl. Recrystallization frommethanol-ether givesN-benzyl-exo-fi-hydroxy-N,2,3,3-tetramethylexo-Z-norbornanamine,hydrochloride, m.p. 164-165 (dec).

Anal. Calcd. for C I-I NOCI: C, 69.79; H, 9.11; Cl,

Found: C, 69.42; H, 8.94; Cl, 11.01. Example 6 N-benzyl-endo-6hydroxy-N,2,3,3- tetramethyl-exo-Z-norbornanamine (VI) and thehydrochloride salt thereof Following the procedure of Example 5, above,5.0 g. of N-benzoyl-endo-6-hydroxy-N,2,3,3-tetramethy1-exo-Z-norbornanamine (V) is treated with 5 g. of lithium aluminumhydride to obtain 4.75 g. ofN-benzylendo-6-hydroxy-N,2,3,3-tetramethyl-exo-Z-norbornanamine (V1), asa colorless oil; the hydrochloride salt thereof recrystallized frommethanol acetone m.p.

89-90 C. (dec.).

Anal. Calcd. for C H NOCl: N, 4.52; CI, 11.44.

Found: N, 4.38; Cl, 11.31. Example 7 N-benzyl-cis-7-hydroxy-N,2,3,3-tetramethyl-exo- 2norbornanamine (X1) and the hydrochloride salt thereofFollowing the procedure of Example 5, above, 4.34 g. ofN-benzoyl-cis-7-hydroxy-N,2,3,3-tetramethylexo-Z-norbornanamine (X) isconverted in nearly quantitative yield toN-benzyl-cis-7-hydroxy-N,2,3,3- tetramethyLexo-Z-norbornanamine (X1),which is converted toN-benzyl-cis-7-hydroxy-N,2,3,3-tetrarnethylexo-2-norbornanamine,hydrochloride, m.p. 151-153 C.

Anal. Calcd. for c,,,H,,Noci; N, 4.52; c1, 11.44.

Found: N, 4.82;C1, 11.63. Example 8 N-benzyl-transJ hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine (XI) and the hydrochloride salt thereof7 Following the procedure of Example 5, above, N- benzoyl-tran s-7-hyclro xy-N ,2 ,3 ,3 -tetram ethyl-exo-2- norbornanamine (111) is convertedin nearly quantitative yield to obtain N-benzyltransJ-hydroxy-N,2,3',3-tetramethyl-exo-2-norbornanamine (X11), and N-benzyl-trans-7-hydroxy-N,2,3,3-tetramethyl-exo-2- norbornanaminehydrochloride. Example 9 Exo-6-hydro xy-N,2,3,3-tetramethyl-exo-2-norbornanamine (V111) and the hydrochloride salt thereof A solution of4.0 g. of N-benzyl-exo-6-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine (VII) is dissolved in about 30ml. of ethanol; 0.75 g. of percent palladium on carbon is added and themixture is shaken with hydrogen at about 45 psig. for about 16 hours oruntil the uptake of hydrogen is complete. The catalyst is removed byfiltration and the filtrate is concentrated in vacuo to giveexo-6-hydroxy-N, 2,3,3- tetramethyl-exo-Z-norbornanamine (VIII) as thefree base. The free base thus obtained is dissolved in ether and treatedwith a slight excess of ethereal hydrogen chloride to precipitate thehydrochloride salt, which is recovered by filtration, washed with etherand dried to give 2.75 g. of exo-6-hydroxy-N,2,3,3-tetramethyl-exo2-norbornanamine, hydrochloride, m.p. 282 C. (dec.).

Anal. Calcd. for c,,H ,No-Hc1; C, 60.11; H, 10.09;

FoundzC, 60.36; H, 10.16; Cl, 16.13.

Example 10 Endo-6-hydroxy-N,2,3,3-tetramethylexo-2-norbornanamine (VIII)and the hydrochloride salt thereof The procedure of Example 9, above, isrepeated using 4.0 g. of N-benzyl-endo-6-hydroxy-N,2,3,3-tetramethyl-exo-2-norbomanamine (V) as the starting mate rial to obtainendo-6-hydroxy-N,-2 ,3 ,3 tetramethyl-exo-2-norbornanamine (VIII) whichis treated with ethereal I-ICl to give 2.10 g. of endo-6- hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, hydrochloride, m.p. 244-247 C.

Anal. Calcd. for C H NO-HCl: C, 60.11; H, 10.09;

Found: C, 59.95;H, 10.26; Cl, 15.91.

Example 11 Cis-7-hydroxy-N,2,3,3-tetramethyl-exo- 2-norbornanamine(XIII) and the hydrochloride salt thereof The procedure of Example 9,above, is repeated using 4.0 g. of N-benzyl-cis-7-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine (XI) as the starting material to obtaincis-7-hydroxy-N-2,3,3-tetramethylexo-2-norbornanamine (XIII) which istreated with ethereal HCl to give 2.30 g. of endo -6-hydroxy- N,2,3,3-tetramethyl-exo-2-norbomanamine, hydrochloride, m.p. 270-275 C.

Anal. Calcd. for C H NO-I-ICI: N, 6.38; CI, 16.14.

Found: N, 6.81;Cl, 16.05.

Example 12 Trans-7-hydroxy-N,2,3,3-tetramethylexo-2-norbornanamine(XIII) and the hydrochloride salt thereof The procedure of Example 9,above, is repeated using 4.0 g. of N-benzyl-trans-7-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine (XII) as the starting material toobtain trans-7-hydroxy-N-2,3,3- tetramethyl-exo-2-norbornanamine (XIII)and trans-7- hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine,hydrochloride.

Example 13 N-benzyl-6-keto-N,2,3,3-tetramethylexo-2-norbornanamine (XVI)and the hydrochloride salt thereof A solution of 10.0 g. ofN-benzyl-endo o-hydroxy- N,2,3,3-tetramethyl-exo-2-norbornanamine (XIV)in 600 ml. of toluene and 150 ml. of cyclohexanone is distilled toremove 100 m1. of toluene. Aluminum isopropoxide (20.0 g.) is then addedand the mixture is heated at reflux for about 1 hour. The reactionmixture is then cooled, poured into ice-water containing excesshydrochloric acid, stirred and the layers allowed to separate. Theaqueous layer is further extracted with ether and then made basic by theaddition of 50 percent aqueous sodium hydroxide solution. The resultingaqueous mixture is extracted with ether. The ether extract is washedwith water and dried over magnesium sulfate. The dried ether solution isevaporated to remove the solvent to give N-benzyl-6-keto-N,2,3,3-tetramethyl-exo-Z-norbornanamine (XVI) as the free base. The free basethus obtained is dissolved in ether and treated with a slight excess ofethereal hydrogen chloride and the crystalline precipitate thus obtainedis recovered by filtration, washed with ether and dried to giveN-benzyl-6-keto-N,2,3,3-tetramethyl-exo-2-norbornanamine, hydrochloride,which is furtherv purified by recrystallization from methanol-ether.

Following the procedure of Example 13 other 6- and 7-hydroxy compoundsof this invention are likewise oxidized to give the corresponding ketocompounds, for example:

N-benzyl-exo-o-hydroxy-N,2,3,3-tetramethyl-exo-2- norbornanamine (XIV)to give N-benzyl-6-keto- N,2,3,3-tetramethyl-exo-2-norbornanamine (XVI)and the hydrochloride salt thereof;

N-benzyl-cis-7-hydroxy-N,2,3,3-tetramethyl-exo-2- norbornanamine (XV) togive N-benzyl-7-keto- N,2 ,3 ,3-tetramethyl-exo-2-norbornanamine (XVII)and the hydrochloride salt thereof;

N-benzyl-trans-7-hydroxy-N,2,3,3-tetramethyl-exo- 2-norbornanamine (XV)to give N-benzyl-7-keto- N,2,3,3-tetramethyl-exo-Z-norbornanamine (XVII)and the hydrochloride salt thereof;

exo-6-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine (XIV) to give6-keto-N-2,3,3-tetramethylexo-2-norbornanamine (XVI) and thehydrochloride salt thereof;

endo-6-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine (XIV) to give6-keto-N,2,3,3-tetramethyl- N,2,3,3-tetramethyl-exo- 2-norbornanamine(XVI) and the hydrochloride thereof;

cis-7-hydroxy-N,2,3 ,3'tetramethyl-exo-Z-norbornanamine (XV) to give7-keto-N,2,3,3-tetramethylexo-2-norbornanamine (XVII) and thehydrochloride salt thereof; and

trans-7-hydroxy-N ,2 ,3 ,3 -tetram ethyl-exo-Z-norbo rnanamine (XV) togive 7-keto-N,2,3,B-tetramethylexo-2-norbornanamine (XVII) and thehydrochloride salt thereof.

Example 14 Exo-6-methoxy-N,2,3,3-tetramethylexo-2-norbornanamine (XXIV)and the hydrochloride salt thereof A solution of 5.46 g. (0.02 mole) ofN-benzoyl-exo- 6-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine(XVIII) in about 150 ml. of methylene chloride is treated with 2.5 g. ofaluminum isopropoxide and then with 100 ml. of a methylene chloridesolution of diazomethane (prepared from 265 ml. of methylene chloride,22.0 g. of N-methyl-N'-nitro-N- nitrosoquanidine, and 70 ml. of 45percent potassium .hydroxide solution). After standing at roomtemperature for about 354 hrs., 100 ml. more methylene chloride solutionof diazomethane is added. The mixture is allowed to stand for about 22hours. The solution is washed with 100 ml. of water, 100 ml. of 10percent sulfuric acid, and twice with 50 ml. of water and dried oversodium sulfate. The methylene chloride solution is chromatographed overflorisi], eluting by the linear gradient method with 6 l. of solvent,Skellysolve B hexanes containing increasing proportions of acetone. Cutsof 200 ml. each are taken and the residues examined by TLC and infraredassays. The cuts containing the desired product are combined to give3.57 g. of N-benzoyl-exo-6-methoxy-N,2,3,3-tetramethyl-exo-2-norbornanamine (XX) which is dissolved in about 50 ml.of ether and reduced with a solution of 4.0 g. of LiAlH in 100 ml. ofether. The mixture, thus obtained is refluxed for about 70 minutes,chilled in a cold bath at and cautiously treated with 25 ml. of waterwhile stirring vigorously. When the mixture is completely white, theinorganic solid is removed by filtration and washed well with ether. Thecombined filtrate and wash are dried over magnesium sulfate and thesolvent is evaporated to yield 2.89 g. of N -be nzyl-exo-6-methoxy-N,2,3 ,3-tetramethyl-exo-2- norbornanamine (XXII) as a white solid. Theproduct thus obtained, (2.89 g.) is dissolved in about 100 ml. ofethanol by warming and reduced with hydrogen and 0.5 g. of 10 percentpalladium on carbon catalyst at about 45 psig. until the uptake ofhydrogen is complete (about 16 hours). The catalyst is removed byfiltration and the filtrate is concentrated in vacuo to give exo-6-methoxy-N,2,3,3-tetramethyl-exo-2-norbornanamine (XXIV) as the freebase. The free base thus obtained is dissolved in ether and treated witha slight excess of ethereal hydrogen chloride to precipitate thehydrochloride salt which is recovered by filtration and recrystallizedfrom methanol-ether to give 1.57 g. ofexo-6-methoxy-N,2,3,3-tetramethyl-ex0-2-norbor- I nanamine,hydrochloride, m.p. 253 C (dec.).

Anal. Calcd. for C H NO'HCI: C, 61.65; H, 10.35;

N, 5.99; CI, 15.17.

Found: C, 61.79; H, 10.78; N, 6.06; CI, 14.99. ExampleEndo-6-methoxy-N,'2,3,B-tetramethylexo-2-norbornanamine (XX) and thehydrochloride salt thereof Following the procedure of Example 14, above5.46 g. (0.02 mole) of N-benzoyl-endo-6-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine (XVIII) is treated with 2.5 g. ofaluminum isopropoxide and then with 100 ml. of diazomethane solution toobtain N-benzylendo-6-methoxy-N,2,3,3-tetramethyl-exo-Z-norbornanamine(XX), which is then reduced with 4.0 g. of lithium aluminum hydride togive N-benzyl-endo-G- methoxy-N,2,3,3-tetramethyl exo-2-norbornanamine(XXII). Compound (XXII) thus obtained is then reduced with hydrogen and0.5 g. of palladium on carbon catalyst to give endo-6-methoxy-N,2,3,3-tetramethyl-exo-Z-norbornanamine (XXIV) as the free base, which istreated with ethereal hydrogen chloride and recrystallized to give 2.21g. of endo-6-methoxy- N ,2 ,3 ,3-tetramethyl-exo-2-norbornanaminde,hydrochloride, m.p. 282 C. (dec.).

Anal. Calcd. for C H NOCl: C, 61.65; H, 10.35; N,

FoundzC, 62.07;I-I, 10.33;N,6.28;Cl, 15.30. Example 16Cis-7-methoxy-N,2,3,3-tetramethylexo.-2-norbornanamine (XXV) and thehydrochloride salt thereof Following the procedure of Example 14, above5.46 g. (0.02 mole) of N-benzoyl-cis-7-hydroxy-N,2,3,3-tetramethyl-exo-Z-norbornanamine (XIX) is treated with 2.5 g. ofaluminum isopropoxide and then with m1. of diazomethane solution toobtain N-benzoylcis-7-methoxy-N,2,3,3-tetramethyl-exo- 2-norbornanamine(XXI), which is then reduced with 4.0 g. of lithium aluminum hydride togive N-benzyl-cis-7- methoxy-N,2,3,3-tetramethyl-exo-2-norbornanarnine(compound XXIII). Compound (XXIII) thus obtained, is then reduced withhydrogen and 0.5 g. of palladium on carbon catalyst to givecis-7-methoxy-N,2,3,3- tetramethyl-exo-2-norbornanamine (XXV) as thefree base, which is treated with ethereal hydrogen chloride andrecrystallized to give 2.09 g. (49 percent yield) ofcis-7-methoxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, hydrochloride,m.p. 282 C. (dec.).

Anal. Calcd. for C, H NOC1: C, 61.65; H, 10.35; N,

Found: C, 61.71; H, 10.26; N, 6.34; CI, 15.14. Example 17Trans-7-methoxy-N, 2,3,3tetramethylexo-2-norbornanamine (XXV) and thehydrochloride salt thereof Following the procedure of Example 14, above5.46 g. (0.02 mole) of N-benzoyl-trans-7-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine (XIX) is treated with 2.5 g. ofaluminum isopropoxide and then with 100 ml. of diazomethane solution toobtain N-benzoyl--trans-7-methoxy-N,2,3,3-tetramethyl-exo-Z-norbornanamine (XXI), which isthen reduced with 4.0 g. of lithium aluminum hydride to giveN-benzyl-trans-7- methoxy-N,2,3,3-tetramethyl-exo-2-norbornanamine(XXIII). Compound (XXIII) thus obtained, is then reduced with hydrogenand 0.5 g. of palladium on carbon catalyst to givetrans-7-methoxy-N,2,3,3- tetramethyl-exo-2-norbornanamine (XXV) as thefree base, which is treated with ethereal hydrogen chloride andrecrystallized to give trans-7-methoxy-N, 2,3,3-tetramethyl-exo-2-norbornanamine, hydrochloride. Example 18N-benzyl-exo6'hydroxy-N,2,3,3- tetramethyl-exo-2-norbornanamine,tosylate A solution of 3 g. of N-benzyl-exo-6-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine (VII) in about 15 ml. ofpyridine is treated with 4.0 g. of ptoluenesulfonyl chloride at roomtemperature for about 22 hrs. The mixture is poured onto 50. g. of iceand stirred. The aqueous phase is decanted from the oily product whichis washed twice with water by stirring and decantation. About 2.0 ml. ofmethanol is then added and the oil is crystallized. The product isrecovered by filtration and washed with a little cold methanol to give3.40 g. of N-benzyl-exo--hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, tosylate, m.p. 62-66 C.; ananalytical sample is obtained by recrystallization from methanol, m.p.67-69 C.

Anal. Calcd. for C I-I NO S: C, 70.22; H, 7.78; N,

Found: C, 70.19; H, 7.94; N, 3.19;8, 7.81. Example 19N-benzyl-endo-6-hydroxy-N,2,3,3- tetramethyl-exo-2-norbornanamine,tosylate Following the procedure of Example 4, above, 1.17 g. ofN-benzyl-endo-6-hydroxy-N,2,3,3-tetrahydro exo-2-norbornanamine (VI) inabout 5 ml. of pyridine is treated with 1.5 g. of p-toluenesulfonylchloride to obtain 1.4 g. of N-benzyl-endo-6-hydroxy-N,2,3,3-tetramethyl-exo-2-norbomanamine, tosylate, m.p. 1 16-1 17 C.

Anal. Calcd. for C l-1 N0 5: C, 70.22; H, 7.78; N,

3.28; S, 7.50. Found: C, 70.34; H, 7.81; N, 3.18; S, 7.38.

Anal. Calcd. for C H NO S: C, 70.22; H, 7.78; N,

3.28; S, 7.50. Found: C, 69.96; H, 7.85; N, 3.45; S, 7.38. Example 21N-benzyl-trans-7-hydroxy-N,2,3,3- tetramethyl-exo-2-norbornanamine,tosylate Following the procedure of Example 4, above, 3.67 g. ofN-benzyl-trans-7-hydroxy-N,2,3,3-tetramethylexo-2-norbornanamine (XII)in about ml. of pyridine is treated with 5.0 g. of p-toluenesulfonylchloride to obtain N-benzyl-trans-7-hydroxy-N,2,3,3-tetramethyl-exo-2-norb ornanamine, tosylate.

We claim:

1. A compound of the formulas:

on; 211, NR NR R 0H; 0H:

TCH; q-CH;

CH, on3

0: CH; and CH3 7GB: C a 0H; 0H.

wherein R is hydrogen, and R, and R are each hydroxy or methoxy, and thepharmacologically acceptable acid addition salts thereof.

2. A compound of the formula:

6. Exo-6-methoxy-N,2,3,3-tetramethyl-exo-2-norbornanamine,hydrochloride, the compound of claim 2 wherein R is hydrogen, R, ismethoxy, and the pharmacologically acceptable acid addition salt is thehydrochloride.

7. A compound of the formula:

wherein R is hydrogen, and R, is hydroxy or methoxy, inclusive, and thepharmacologically acceptable acid addition salts thereof.

8. Endo-6-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, the compoundof claim 7 wherein R is hydrogen and R, is hydroxy.

9. Endo-6-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine,hydrochloride, the compound of claim 7 wherein R is hydrogen, R, ishydroxy, and the pharmacologically acceptable acid addition salt is thehydrochloride.

l0. Endo-6-methoxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, thecompound of claim 7 wherein R is hydrogen and R, is methoxy.

1 l. Endo-6-methoxy-N,2,3,3-tetramethyl-exo-2-norbornanamine,hydrochloride, the compound of claim 7 wherein R is hydrogen, R, ismethoxy, and the pharmacologically acceptable acid addition salt is thehydrochloride.

12. A compound of the formula:

wherein R is hydrogen, and R is hydroxy or methoxy inclusive, and thepharmacologically acceptable acid addition salts thereof.

13. Trans-7-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, thecompound of claim 12 wherein R is hydrogen and R is hydroxy.

M. Trans-7-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine,hydrochloride, the compound of claim 12 wherein R is hydrogen, R ishydroxy, and the pharmacologically acceptable acid addition salt is thehydrochloride.

l5. Trans-7-methoxy-N,2,3,3-tetramethyl-exo-2- norbornanamine, thecompound of claim 12 wherein R is hydrogen and R is methoxy.

16. Trans-7-methoxy-N,2,3,3-tetramethyl-exo-2- norbornanamine,hydrochloride, the compound of claim 12 wherein R is hydrogen, R ismethoxy, and the pharmacologically acceptable acid addition salt is thehydrochloride.

17. A compound of the formula:

CH: I l-R CHa CH; CH:

7 hydrogen and R is methoxy.

21. Cis-7-methoxy-N,2,3,3-tetramethyl-exo-2-norbornanamine,hydrochloride, the compound of claim- 17 wherein R is hydrogen, R ismethoxy, and the pharmacologically acceptable acid addition salt is thehydrochloride.

22. A compound of the formula:

Cis-7-hydroxy-N ,2 ,3 ,3 -te-tramethyl-exo-Z-nor wherein R is hydrogen,and the pharmacologically acceptable acid addition salts thereof.

23. 6-Keto-N,2,3,3-tetramethyl-exo-2-norbornanamine, the compound ofclaim 22 wherein R is hydrogen.

24. -Keto-N ,2 ,3 ,3 -tetramethyl-exo-2 -norb ornanamine, hydrochloride,the compound of claim 22 wherein R is hydrogen, and thepharmacologically acceptable acid addition salt is the hydrochloride.

25. A compound of the formula:

wherein R is hydrogen, and the pharmacologically acceptable acidaddition salts thereof.

26. 6-Keto'N ,2 ,3 ,3 -tetram ethyl-exo-Z-norbornanamine, the compoundof claim 25 wherein R is hydrogen.

27. 6-Keto-N,2 ,3 ,3-tetramethyl-exo-Z-norbornanamine, hydrochloride,the compound of claim 25 wherein R is hydrogen, and thepharmacologically acceptable acid addition salt is the hydrochloride.

1. A compound of the formulas:
 2. A compound of the formula: 3.Exo-6-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, the compound ofclaim 2 wherein R is hydrogen and R1 is hydroxy. 4.Exo-6-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, hydrochloride,the compound of claim 2 wherein R is hydrogen, R1 is hydroxy, and thepharmacologically acceptable acid addition salt is the hydrochloride. 5.Exo-6-methoxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, the compound ofclaim 2 wherein R is hydrogen and R1 is methoxy. 6.Exo-6-methoxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, hydrochloride,the compound of claim 2 wherein R is hydrogen, R1 is methoxy, and thepharmacologically acceptable acid addition salt is the hydrochloride. 7.A compouNd of the formula: 8.Endo-6-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, the compound ofclaim 7 wherein R is hydrogen and R1 is hydroxy. 9.Endo-6-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, hydrochloride,the compound of claim 7 wherein R is hydrogen, R1 is hydroxy, and thepharmacologically acceptable acid addition salt is the hydrochloride.10. Endo-6-methoxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, thecompound of claim 7 wherein R is hydrogen and R1 is methoxy. 11.Endo-6-methoxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, hydrochloride,the compound of claim 7 wherein R is hydrogen, R1 is methoxy, and thepharmacologically acceptable acid addition salt is the hydrochloride.12. A compound of the formula: 13.Trans-7-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, the compoundof claim 12 wherein R is hydrogen and R2 is hydroxy. 14.Trans-7-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, hydrochloride,the compound of claim 12 wherein R is hydrogen, R2 is hydroxy, and thepharmacologically acceptable acid addition salt is the hydrochloride.15. Trans-7-methoxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, thecompound of claim 12 wherein R is hydrogen and R2 is methoxy. 16.Trans-7-methoxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, hydrochloride,the compound of claim 12 wherein R is hydrogen, R2 is methoxy, and thepharmacologically acceptable acid addition salt is the hydrochloride.17. A compound of the formula: 18.Cis-7-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, the compound ofclaim 17 wherein R is hydrogen and R2 is hydroxy. 19.Cis-7-hydroxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, hydrochloride,the compound of claim 17 wherein R is hydrogen, R2 is hydroxy, and thepharmacologically acceptable acid addition salt is the hydrochloride.20. Cis-7-methoxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, the compoundof claim 17 wherein R is hydrogen and R2 is methoxy. 21.Cis-7-methoxy-N,2,3,3-tetramethyl-exo-2-norbornanamine, hydrochloride,the compound of claim 17 wherein R is hydrogen, R2 is methoxy, and thepharmacologically acceptable acid addition salt is the hydrochloride.22. A compound of the formula: 23.6-Keto-N,2,3,3-tetramethyl-exo-2-norbornanamine, the compound of claim22 wherein R is hydrogen. 24.6-Keto-N,2,3,3-tetramethyl-exo-2-norbornanamine, hydrochloride, thecompound of claim 22 wherein R is hydrogen, and the pharmacologicallyacceptable acid addition salt is the hydrochloride.
 25. A compound ofthe formula:
 26. 6-Keto-N,2,3,3-tetramethyl-exo-2-norbornanamine, thecompound of claim 25 wherein R is hydrogen.